1. Field of the Invention
The present invention relates to novel glycosides of catechol estrogens, a process for the manufacture thereof, and a medicament comprising at least one of the glycosides for the prevention and treatment of lipid peroxide- and free radical-related diseases.
2. Related Arts
It is known that lipid peroxides are causative of ischemia-reperfusion injury, ischemic heart disease, atherosclerosis, retinopathy in infant, siderosis, cataract, hepatitis, pancreatitis, diabetic microangiopathy, melanoderma, liver spots, pre-eclampsia and aging itself. Therefore, the prevention of lipid peroxidation by use of suitable antioxidants is beneficial for the prophylactic and treatment of such diseases. Thus, it is in need to develop effective antioxidants as medical compound. In 1987, Yoshino et al. reported that estrogens and their metabolites catechol estrogens are effective to prevent an increase in lipid peroxide levels in mice [K. Yoshino et al., "J. Clin. Biochem. Nutr.", Vol. 3, pages 233-240 (1987)].
Thus, estrogens and catechol estrogens were thought to be hopeful for clinical application, however, the following disadvantages thereof make it difficult: Since these compounds are scarcely soluble in water, it is difficult to prepare an injection. Estrogens are not applicable to men because of their activity as a female hormone. Although estrogenic activity of catechol estrogens is almost nil, they are unstable against exposure to air and light so that the development of a medicament comprising catechol estrogen is not progressing. In addition, it is known that a half life of catechol estrogens in human blood is very short due to high susceptibility to be taken up into red blood cells and to be metabolized by catechol-O-methyl-transferase in the cells. Accordingly, these characteristics of catechol estrogens make it difficult to develop useful medicaments, even though they have a potent antioxidant activity.
As to organic synthesis of catechol estrogens, not a few papers were reported in literatures as listed below:
(a) J. Fishman, "J. Am. Chem. Soc.", 80, 1213 (1958), PA1 (b) P. N. Rao, et al., "Tetrahedron", 10, 144 (1960), PA1 (c) J. Fishman, "J. Org. Chem.", 25, 585 (1960), PA1 (d) T. Nambara, et al., "Chem. Pharm. Bull.", 18, 474 (1970), PA1 (e) T. Nambara, et al., "Chem. Pharm. Bull.", 18, 1191 (1970), PA1 (f) I. Yoshizawa, et al., "Chem. Pharm. Bull.", 20, 1842 (1972), PA1 (g) K. Kovacs, et al., "Acta Phys. Chem.", 19, 287 (1973), PA1 (h) H. G. Gelbke, et al., "Steroids", 21, 205 (1973), PA1 (i) G. Stubenrauch, et al., "Steroids", 28, 733 (1976), PA1 (j) R. G. Xie, et al., "Steroids", 40, 389 (1982), and PA1 (k) T. Ohkubo, et al., "Chem. Pharm. Bull.", 36, 419 (1988), PA1 (a) The starting material is available at reasonable cost; PA1 (b) The number of reaction steps is minimum; PA1 (c) Reaction time is as short as possible, and PA1 (d) Yield is satisfactory.
Among the methods previously available, only two methods gave a relatively good yield of 50 to 60% for the preparation of catechol estrogens. Namely, the method described in Reference (j) includes the Friedel-Crafts reaction of estradiol to form 2-acetylestradiol 17-acetate (yield: 57.3%) followed by the Dakin reaction at pH 8.2-8.5 to form 2-hydroxyestradiol 17-acetate (yield: 85.2%). In this case, the overall yield was 49%. According to the method described in Reference (f), estradiol was reacted with benzoyl peroxide to form 2-hydroxyestradiol 2-monobenzoate and followed by hydrolysis to give 2-hydroxyestradiol. The overall yield in this process was 60%.
When derivatives of catechol estrogens are synthesized, it is important to prepare desirable intermediates thereof, wherein a suitable protective group is introduced into desired position. For example, Nambara et al. [References (d) and (e)] described the preparation of 2-acetoxyestrogens 3-alkyl ether and 3-acetoxy-2-alkoxy-1,3,5(10)-estratriene compounds from corresponding acetyl estrogens by Baeyer-Villiger oxidation in yields of 65-75% and 56-60%, respectively, in order to introduce desired substitution into desired positions.
For the preparation of 2-hydroxyestrogen 3-glycoside, 2-benzyloxyestrogen is an important intermediate. The procedure described in References (d) and (e) involved 11 reaction steps for the synthesis of 2-benzyloxyestradiol 17-acetate from 3-deoxyestradiol acetate and its overall yield was only 6%, then, 2-benzyloxyestradiol 17-acetate was further subjected to glucuronidation to form 2-hydroxyestradiol 3-glucuronide in a overall yield of 0.33%.
Thus, the procedures previously reported are not suitable for the manufacture thereof, because starting material is expensive, the process involves many reaction steps, and yield is not satisfactory.